Paricalcitol (DB00910): A Comprehensive Monograph on a Selective Vitamin D Receptor Activator

1.0 Executive Summary

Paricalcitol is a synthetic, biologically active analog of vitamin D, chemically identified as 19-nor-1α,25-dihydroxyvitamin D2.[1] It functions as a selective agonist for the Vitamin D Receptor (VDR), a nuclear receptor that modulates gene expression in a wide array of tissues.[1] The primary clinical application of paricalcitol is the prevention and treatment of secondary hyperparathyroidism (SHPT), a common and serious complication of chronic kidney disease (CKD) in patients with Stage 3, 4, or 5 disease.[1]

The therapeutic rationale for paricalcitol's development was to create a VDR activator that could potently suppress the synthesis and secretion of parathyroid hormone (PTH) while exhibiting a reduced impact on intestinal calcium absorption and bone calcium mobilization. This selective action aims to mitigate the risks of hypercalcemia and hyperphosphatemia, which are dose-limiting toxicities of older, non-selective VDR activators like calcitriol, and are associated with an increased risk of vascular calcification and cardiovascular mortality.[4]

The principal safety concerns associated with paricalcitol therapy are directly related to its mechanism of action and include hypercalcemia, hyperphosphatemia, and the potential for excessive PTH suppression, which can lead to adynamic bone disease.[8] Its metabolism is significantly mediated by the cytochrome P450 3A4 (CYP3A4) enzyme, creating a high potential for clinically significant drug-drug interactions, particularly in the CKD population, which is characterized by polypharmacy. This necessitates diligent patient monitoring and careful dose adjustments when co-administered with potent CYP3A4 inhibitors or inducers.[10]

Beyond its established role in managing SHPT, emerging research is actively investigating the pleiotropic effects of paricalcitol. Leveraging the ubiquitous expression of the VDR, investigational studies are exploring its potential anti-inflammatory, anti-fibrotic, and immunomodulatory properties. This has led to clinical research into its applications in improving cardiovascular outcomes and as an adjunctive therapy in oncology, most notably for its ability to modulate the tumor microenvironment in pancreatic cancer.[12]

2.0 Drug Identity and Physicochemical Properties

[A precise understanding of the chemical and physical characteristics of paricalcitol is fundamental to appreciating its formulation, biological activity, and analytical identification.]

2.1 Nomenclature and Identifiers

[Paricalcitol is recognized by a variety of names and unique identifiers across chemical and pharmaceutical databases, ensuring its unambiguous identification for regulatory, clinical, and research purposes.]

• Generic Name: Paricalcitol [1]
• Chemical Name: 19-nor-1α,25-dihydroxyvitamin D2 [1]
• Systematic (IUPAC) Name: Due to its complex steroidal structure, multiple IUPAC conventions are used, including (1R,3R,7E,17β)-17--9,10-secoestra-5,7-diene-1,3-diol [2] and (1R,3R)-5--7a-methyl-2,3,3a,5,6,7-hexahydro-1H-inden-4-ylidene]ethylidene]cyclohexane-1,3-diol.[3]
• Trade Name: The originator product is marketed under the brand name Zemplar®.[1]
• Database Identifiers: Key identifiers include its DrugBank Accession Number (DB00910), CAS (Chemical Abstracts Service) Registry Number (131918-61-1), PubChem Compound ID (5281104), and ChEMBL ID (CHEMBL1200622).[1]

2.2 Chemical Structure and Formulation

Paricalcitol is a small molecule drug belonging to the Vitamin D and Analogues class.[1] Structurally, it is classified as a seco-cholestane and a hydroxy seco-steroid, functionally related to vitamin D2.[3] It is a synthetic analog of calcitriol (1,25-dihydroxyvitamin D3), the body's endogenous active vitamin D hormone. Paricalcitol is distinguished by two critical structural modifications: the removal of the exocyclic methylene group from the A-ring (making it a 19-nor compound) and alterations to the side chain to match that of vitamin D2 (ergocalciferol).[1][ These modifications are integral to its selective biological activity.]

Its molecular formula is C27​H44​O3​.[1] The average molecular weight is 416.6365 g/mol, and the monoisotopic mass is 416.329045274 g/mol, often rounded to 416.64 or 416.65 g/mol in product literature.[1] Physically, it appears as a white to off-white crystalline powder or solid.[20]

The physicochemical properties of paricalcitol dictate its formulation requirements. It is practically insoluble in water (<0.1 mg/mL) but demonstrates solubility in organic solvents such as ethanol and dimethyl sulfoxide (DMSO).[20] This lipophilicity necessitates specific formulations for both oral (soft gelatin capsules containing the drug in a lipid vehicle) and intravenous (aqueous solution with solubilizing agents) administration.[5] The precise stereochemistry of the molecule, defined by its InChI (International Chemical Identifier) and SMILES (Simplified Molecular-Input Line-Entry System) strings, is crucial for its high-affinity binding to the VDR and its subsequent biological effects.[2]

Table 2.1: Physicochemical and Structural Properties of Paricalcitol

Property	Value	Source(s)
IUPAC Name	(1R,3R)-5--7a-methyl-2,3,3a,5,6,7-hexahydro-1H-inden-4-ylidene]ethylidene]cyclohexane-1,3-diol	3
CAS Number	131918-61-1	1
DrugBank ID	DB00910	1
Molecular Formula	C27​H44​O3​	1
Average Molecular Weight	416.64 g/mol	1
Appearance	White to off-white crystalline powder/solid	20
Solubility (DMSO)	2 mg/mL to 100 mg/mL	20
Solubility (Ethanol)	1 mg/mL to 12.5 mg/mL	20
Solubility (Water)	Insoluble (<0.1 mg/mL)	20
InChIKey	BPKAHTKRCLCHEA-UBFJEZKGSA-N	2
SMILES	CC@H[C@H]1CC[C@@H]\2[C@@]1(CCC/C2=C\C=C3CO)C

3.0 Clinical Pharmacology

[The clinical utility of paricalcitol is derived from its specific interactions with the Vitamin D Receptor and the downstream physiological consequences of this interaction. Its pharmacodynamic profile was intentionally engineered to optimize the treatment of secondary hyperparathyroidism.]

3.1 Mechanism of Action (Pharmacodynamics)

[Paricalcitol exerts its biological effects by acting as a potent agonist of the Vitamin D Receptor (VDR). The VDR is a member of the nuclear receptor superfamily of transcription factors and is expressed in a vast range of human tissues, including the primary targets for mineral homeostasis—parathyroid gland, intestine, kidney, and bone—as well as in the cardiovascular system, immune cells, and prostate, among others. This ubiquitous distribution is responsible for the pleiotropic effects of VDR activation.]

[The mechanistic cascade begins when paricalcitol binds to the cytosolic VDR. This binding event induces a conformational change in the receptor, leading to its activation. The activated ligand-receptor complex then translocates to the cell nucleus, where it forms a heterodimer with another nuclear receptor, the Retinoid X Receptor (RXR). This VDR/RXR heterodimer functions as a transcription factor, binding to specific DNA sequences known as Vitamin D Response Elements (VDREs) located in the promoter regions of target genes.]

[The primary therapeutic action of paricalcitol in the treatment of SHPT occurs within the parathyroid gland. The binding of the paricalcitol-VDR/RXR complex to the VDRE of the parathyroid hormone gene directly suppresses the transcription of pre-pro-PTH messenger RNA (mRNA). This leads to a reduction in the synthesis and subsequent secretion of PTH into the bloodstream, thereby addressing the hallmark pathology of SHPT.]

3.2 Rationale for Selectivity and Reduced Calcemic Effect

A central feature of paricalcitol is its designation as a selective[ VDR activator. This selectivity is not based on differential binding affinity for the VDR but rather on a differential downstream response in various target tissues, a concept rooted in its unique chemical structure. Compared to the endogenous VDR activator, calcitriol, paricalcitol possesses key modifications to its side chain (D2-like) and its A-ring (19-nor).]

[These structural alterations are thought to confer a therapeutic advantage. While maintaining potent efficacy in suppressing PTH gene transcription in the parathyroid gland, paricalcitol is designed to be less active than calcitriol at VDRs in the intestine and bone. Consequently, it has a reduced tendency to stimulate intestinal calcium absorption and mobilize calcium from bone. This differential activity profile creates a wider therapeutic window, allowing clinicians to administer doses sufficient to control elevated PTH levels while minimizing the risk of inducing hypercalcemia and hyperphosphatemia—common and dangerous side effects of non-selective vitamin D therapy.]

[This concept of tissue selectivity extends to the cardiovascular system. Vascular calcification is a major contributor to morbidity and mortality in CKD patients. Experimental in vitro studies have provided evidence that paricalcitol may have a more favorable vascular profile than calcitriol. In one key study using cultured vascular smooth muscle cells (VSMCs), calcitriol was shown to promote calcification, whereas paricalcitol did not exhibit this effect under the same conditions. This suggests that selective VDR activation may help avoid the pro-calcific effects seen with older agents, potentially offering a cardiovascular benefit.]

[However, a notable disconnect exists between this compelling preclinical and mechanistic rationale and the evidence from large-scale clinical data synthesis. The structural modifications of paricalcitol were explicitly designed to uncouple PTH suppression from significant effects on calcium and phosphorus homeostasis. This forms the core principle behind its development and marketing. Yet, a comprehensive meta-analysis published in 2016, which pooled data from 10 randomized controlled trials involving 734 patients, found no statistically significant superiority of paricalcitol over other active, non-selective VDRAs in achieving target PTH reduction or in the incidence of hypercalcemia or elevated serum mineral levels. This does not necessarily invalidate the drug's mechanism but suggests that the therapeutic landscape of CKD is far more complex than a single receptor interaction. In clinical practice, patients are managed with a combination of therapies, including various phosphate binders, dietary restrictions, and dialysis modalities. These confounding factors, along with heterogeneity in patient populations and trial designs, may blunt or obscure the relatively subtle mechanistic advantages of selectivity, making them difficult to detect consistently at a population level. The clinical benefit of paricalcitol may therefore be more nuanced, potentially being most pronounced in specific patient subgroups or as part of an integrated management strategy, rather than representing a universally superior effect across all patients.]

4.0 Pharmacokinetic Profile (ADME)

[The absorption, distribution, metabolism, and excretion (ADME) profile of paricalcitol defines its dosing frequency, potential for drug interactions, and behavior in specific patient populations, particularly those with renal impairment.]

4.1 Absorption

[Paricalcitol is well absorbed following oral administration. In healthy individuals, the mean absolute bioavailability of the oral capsule is approximately 72%. In the target population of CKD Stage 5 patients on hemodialysis (HD) or peritoneal dialysis (PD), bioavailability is even higher, at 79% and 86%, respectively.]

[The presence of food has a minimal impact on the extent of absorption. When administered with a high-fat meal, the peak plasma concentration (Cmax​) and total exposure (Area Under the Curve, AUC) remain unchanged. However, the time to reach peak concentration (Tmax​) is delayed by approximately 2 hours. This finding indicates that the oral formulation can be administered without regard to meals, simplifying the dosing regimen for patients. Intravenous administration, used in the dialysis setting, provides immediate and 100% bioavailability.]

4.2 Distribution

[Once in the systemic circulation, paricalcitol is extensively bound to plasma proteins, with a binding fraction exceeding 99.8%. This high degree of protein binding means that only a very small fraction of the drug is "free" or unbound to exert its biological effect at any given time. It also implies that paricalcitol is not significantly removed from the blood during hemodialysis. The apparent volume of distribution (]

[Vd​) is approximately 34 L in healthy subjects and ranges from 44 to 46 L in patients with CKD, indicating that the drug distributes into tissues beyond the plasma compartment.]

4.3 Metabolism

[Paricalcitol undergoes extensive metabolism, with only about 2% of the parent drug being eliminated unchanged. The metabolic pathways are complex and involve multiple enzymes located in both hepatic and non-hepatic tissues. The key enzymes responsible for its biotransformation are mitochondrial CYP24, the major drug-metabolizing enzyme CYP3A4, and the phase II enzyme UGT1A4 (UDP-glucuronosyltransferase 1A4).]

[Metabolism proceeds via several routes, including 24(R)-hydroxylation, 24,26- and 24,28-dihydroxylation, and direct glucuronidation. The main metabolite identified in human plasma is 24(R)-hydroxy paricalcitol, which has been shown to be less pharmacologically active than the parent compound in animal models of PTH suppression. The significant role of CYP3A4 in paricalcitol's clearance is the primary reason for its susceptibility to clinically important drug-drug interactions. In vitro studies have shown that at therapeutic concentrations, paricalcitol itself is not a meaningful inhibitor of major CYP isozymes, suggesting a low risk of it affecting the metabolism of other drugs.]

4.4 Elimination

[The primary route of elimination for paricalcitol and its metabolites is via hepatobiliary excretion into the feces. Following administration of a radiolabeled dose, approximately 70% to 74% of the radioactivity is recovered in the feces, while a smaller fraction, 16% to 18%, is recovered in the urine, almost entirely as metabolites.]

[The elimination half-life (t1/2​) of paricalcitol varies substantially depending on the patient population. In healthy subjects with normal renal function, the half-life is relatively short, ranging from 4 to 6 hours. In contrast, the half-life is significantly prolonged in patients with CKD. For patients with CKD Stage 3 or 4 receiving the oral formulation, the mean elimination half-life is extended to 17-20 hours. In CKD Stage 5 patients on dialysis receiving the intravenous formulation, the half-life is approximately 14-15 hours. This prolonged half-life in the target patient population is a key pharmacokinetic feature that supports the less-frequent dosing regimens, such as three times weekly, commonly used in clinical practice.]

Table 4.1: Summary of Paricalcitol Pharmacokinetic Parameters

[Data compiled from. N/A: Not Applicable or Not Available.]

5.0 Clinical Efficacy and Therapeutic Indications

[The clinical development of paricalcitol was focused on addressing the significant unmet need for effective and safer management of secondary hyperparathyroidism in the growing population of patients with chronic kidney disease.]

5.1 Primary Indication: Secondary Hyperparathyroidism (SHPT) in CKD

[Paricalcitol is approved by the U.S. Food and Drug Administration (FDA) for the prevention and treatment of secondary hyperparathyroidism associated with chronic kidney disease. The approvals are specific to the formulation and disease stage:]

• Oral Capsules:[ Indicated for patients with CKD Stages 3 and 4, as well as for patients with CKD Stage 5 who are on hemodialysis or peritoneal dialysis.]
• Intravenous Injection:[ Indicated for patients with CKD Stage 5 on hemodialysis.]

[The evidence supporting these indications comes from a series of Phase 3 and Phase 4 clinical trials. These studies consistently demonstrated the safety and efficacy of paricalcitol in significantly reducing serum intact PTH (iPTH) levels compared to placebo in the target populations. For the oral formulation, trials have successfully evaluated both daily and three-times-weekly dosing strategies, providing flexibility in clinical practice.]

[The overarching therapeutic goal is to titrate paricalcitol to lower iPTH levels into the target range recommended by clinical practice guidelines, such as those from the Kidney Disease Outcomes Quality Initiative (K/DOQI), which suggest a range of 150–300 pg/mL for dialysis patients. A critical component of this goal is achieving PTH control while simultaneously maintaining serum calcium and phosphorus concentrations within their respective normal limits to avoid the adverse consequences of mineral imbalance.]

5.2 Comparative Efficacy and Limitations

[While paricalcitol was developed to offer a safer alternative to older vitamin D compounds, its position relative to these agents in terms of efficacy is nuanced. A systematic review published in 2016 concluded that there was insufficient evidence to definitively demonstrate a clinical advantage of paricalcitol over non-selective vitamin D derivatives for the treatment of SHPT. This conclusion is consistent with the findings of the meta-analysis discussed previously, which failed to show a statistically significant superiority in PTH reduction or a lower incidence of hypercalcemia when compared to other active VDRAs.]

[Despite the lack of definitive evidence for superiority from these pooled analyses, the introduction of paricalcitol was a significant advancement in the field. It provided clinicians with a valuable therapeutic alternative to calcitriol, particularly for patients who are prone to developing hypercalcemia or hyperphosphatemia with non-selective agents. Its place in therapy is well-established, often used as a first- or second-line VDR activator depending on institutional protocols, formulary status, and patient-specific factors such as baseline serum calcium and phosphorus levels. The choice between paricalcitol and other VDRAs often involves a clinical judgment that balances the need for PTH suppression against the risk of mineral disturbances in an individual patient.]

6.0 Comprehensive Safety Profile and Risk Management

[The safety profile of paricalcitol is intrinsically linked to its potent pharmacologic activity. Effective risk management requires a thorough understanding of its adverse effects, contraindications, and potential for drug interactions, coupled with diligent patient monitoring.]

6.1 Adverse Reactions

[The adverse events observed with paricalcitol are generally extensions of its vitamin D-like effects. The profile differs slightly between the oral and intravenous formulations, reflecting different patient populations and routes of administration.]

[For the oral formulation used in pre-dialysis CKD patients (Stages 3 and 4), the most common adverse reactions reported at a higher frequency than placebo in clinical trials included diarrhea, hypertension, dizziness, and vomiting. Other commonly reported events across studies include edema, headache, and taste alterations.]

[For the intravenous formulation used in dialysis patients (CKD Stage 5), the safety profile reflects a more critically ill population. Common adverse events include nausea, vomiting, edema, gastrointestinal hemorrhage, chills, fever, and infections such as sepsis and pneumonia. Cardiovascular events like palpitations have also been noted.]

[Serious adverse events are primarily related to disturbances in mineral metabolism. Acute hypercalcemia is the most significant risk and can precipitate life-threatening cardiac arrhythmias and seizures. Severe allergic reactions, including rash, urticaria, and angioedema (including laryngeal edema), have been reported in post-marketing experience. Other serious events noted include severe mood changes (agitation, confusion) and gastrointestinal bleeding.]

Table 6.1: Incidence of Common Adverse Reactions (≥2%) from Placebo-Controlled Trials (IV Formulation)

[Data adapted from placebo-controlled studies in CKD patients on dialysis.]

6.2 Contraindications and Precautions

[The use of paricalcitol is strictly contraindicated in patients with:]

• [Evidence of vitamin D toxicity.]
• [Pre-existing hypercalcemia.]
• [Known hypersensitivity to paricalcitol or any of its excipients.]

[Several critical warnings and precautions must be observed during therapy:]

• Hypercalcemia:[ This is the most significant and predictable toxicity. It can be exacerbated by the concomitant use of high-dose calcium-containing phosphate binders, calcium supplements, or thiazide diuretics. Frequent monitoring of serum calcium is mandatory, especially during dose initiation and titration.]
• Digitalis Toxicity:[ Hypercalcemia of any cause potentiates the toxic effects of digitalis glycosides (e.g., digoxin), increasing the risk of cardiac arrhythmias. Extreme caution and heightened monitoring of serum calcium and signs of digitalis toxicity are required when these agents are used together.]
• Adynamic Bone Disease:[ Excessive suppression of PTH to abnormally low levels can disrupt normal bone turnover, leading to adynamic bone disease, which is characterized by an increased risk of fractures. PTH levels must be monitored periodically to prevent over-suppression.]
• Aluminum Toxicity:[ Paricalcitol may increase the gastrointestinal absorption of aluminum. Therefore, the chronic use of aluminum-containing preparations (e.g., some antacids and phosphate binders) should be avoided to prevent aluminum accumulation and potential bone toxicity.]

6.3 Management of Overdose

[An overdose of paricalcitol will manifest as signs and symptoms of hypercalcemia, hypercalciuria, and hyperphosphatemia. Early symptoms may include weakness, headache, somnolence, nausea, vomiting, dry mouth, constipation, and a metallic taste. Treatment is primarily supportive and involves immediate discontinuation of the drug. Management strategies include instituting a low-calcium diet, withdrawing calcium supplements, and providing hydration. Serum calcium levels should be monitored frequently until they return to the normal range.]

6.4 Significant Drug Interactions

[The polypharmacy common in CKD patients creates a high-risk environment for drug-drug interactions with paricalcitol. A particularly concerning scenario arises from the intersection of paricalcitol's metabolism, the common use of certain drug classes in this population, and the consequences of hypercalcemia. This can be conceptualized as a "high-risk triad." The process begins with the patient, who often has multiple comorbidities like heart failure and is susceptible to infections. The first element of the triad is paricalcitol, a drug whose clearance is dependent on the CYP3A4 enzyme. The second element is a potent CYP3A4 inhibitor, such as the antibiotic clarithromycin or the antifungal ketoconazole, which may be prescribed to treat an infection. The pharmacokinetic consequence of this combination is the inhibition of paricalcitol's metabolism, leading to an acute and unexpected rise in its plasma concentrations. This, in turn, has a pharmacodynamic consequence: the elevated drug levels cause excessive VDR activation, resulting in hypercalcemia. The third element of the triad is a drug like digoxin, commonly used for heart failure. The acute hypercalcemia dramatically potentiates the action of digoxin on the heart, substantially increasing the risk of life-threatening digitalis toxicity and cardiac arrhythmias. This predictable cascade underscores that the safety of paricalcitol depends not only on its intrinsic properties but also on vigilant management of the patient's entire medication regimen.]

Table 6.2: Clinically Significant Drug-Drug Interactions with Paricalcitol

Interacting Agent/Class	Mechanism of Interaction	Clinical Management/Recommendation	Source(s)
Strong CYP3A4 Inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, ritonavir)	Inhibition of CYP3A4-mediated metabolism, leading to increased plasma concentrations and exposure of paricalcitol.	Use with caution. Dosage adjustment of paricalcitol may be needed. Monitor iPTH and serum calcium concentrations more frequently when initiating or discontinuing a strong CYP3A4 inhibitor.
Bile Acid Sequestrants (e.g., cholestyramine, colesevelam)	May bind to oral paricalcitol in the gut, impairing its absorption and reducing its efficacy.	Administer oral paricalcitol at least 1 hour before or 4 to 6 hours after the bile acid sequestrant to minimize interaction.
Thiazide Diuretics (e.g., hydrochlorothiazide, bendroflumethiazide)	Decrease urinary calcium excretion, which can potentiate the hypercalcemic effect of paricalcitol.	Increased risk of hypercalcemia. Use concomitantly with caution and monitor serum calcium levels closely.
Digitalis Glycosides (e.g., digoxin)	Hypercalcemia induced by paricalcitol potentiates the risk of digitalis toxicity and cardiac arrhythmias.	Use with extreme caution. Monitor patients for signs of digitalis toxicity and monitor serum calcium frequently, especially when initiating or adjusting the paricalcitol dose.
Calcium-Containing Preparations & Other Vitamin D Compounds	Additive pharmacodynamic effects, increasing the risk of hypercalcemia and hyperphosphatemia.	Concomitant use should be avoided or managed with extreme care. Prescription-based vitamin D compounds should be withheld during paricalcitol therapy.
Mineral Oil	May interfere with the intestinal absorption of fat-soluble vitamins and their analogs, including oral paricalcitol.	Administer oral paricalcitol at least 1 hour before or 4 to 6 hours after mineral oil.

7.0 Dosage, Administration, and Monitoring

[The clinical application of paricalcitol requires a highly individualized approach to dosing and a rigorous monitoring schedule to ensure efficacy while minimizing the risks of toxicity.]

7.1 Formulations and Strengths

[Paricalcitol is available in two distinct formulations to accommodate different clinical settings and patient needs:]

• Oral:[ Available as soft gelatin capsules in strengths of 1 mcg and 2 mcg. A 4 mcg capsule was previously available but has been discontinued. The capsules contain excipients such as gelatin, glycerin, and various iron oxides for coloring.]
• Intravenous (IV):[ Supplied as a clear, colorless solution for injection. It is available in single-dose vials containing 2 mcg/mL or 5 mcg/mL, and in a multi-dose vial containing 10 mcg/2 mL (5 mcg/mL).]

7.2 Dosing Regimens

[The guiding principle of paricalcitol therapy is that the dosage must be individualized for each patient and carefully titrated based on serial measurements of serum or plasma iPTH, serum calcium, and serum phosphorus. The dosing strategies for initiation and titration are complex and vary significantly depending on the CKD stage, patient age, formulation, and baseline iPTH level.]

[Before initiating therapy, it is crucial to ensure the patient's serum calcium is not above the upper limit of normal. The IV formulation is administered as a bolus dose through a hemodialysis vascular access port and should not be given more frequently than every other day. The oral formulation can be given daily or three times a week (but not on consecutive days).]

Table 7.1: Dosing and Titration Guidelines for Paricalcitol (Oral and IV)

[Guidelines compiled and simplified from. Clinicians must consult full prescribing information for complete details.]

7.3 Essential Patient Monitoring

[Rigorous laboratory monitoring is the cornerstone of safe and effective paricalcitol therapy.]

• Initiation and Titration Phase:[ During the initial phase of treatment or following any dose adjustment, serum calcium and phosphorus levels should be determined frequently (e.g., twice weekly). Serum or plasma iPTH should be measured every 2 to 4 weeks to guide titration.]
• Maintenance Phase:[ Once a stable maintenance dose has been established, the frequency of monitoring can be reduced. Current recommendations are to measure serum calcium and phosphorus at least monthly and iPTH every 3 months.]
• Special Circumstances:[ More frequent monitoring of iPTH and serum calcium is explicitly recommended for patients who are initiating or discontinuing therapy with a known strong CYP3A4 inhibitor, due to the high risk of altered paricalcitol exposure.]

8.0 Regulatory Status and Commercial Landscape

[The development and marketing of paricalcitol reflect its establishment as a key therapeutic agent in the management of complications of chronic kidney disease.]

8.1 FDA Approval History

[Paricalcitol was developed by Abbott Laboratories and received its first marketing authorization from the U.S. Food and Drug Administration (FDA) under the brand name Zemplar®.]

• Zemplar® Intravenous (IV) Injection: First approved on April 17, 1998[, under New Drug Application (NDA) 20-819. Additional strengths and presentations of the injection were subsequently approved in February 2000.]
• Zemplar® Oral Capsules: The oral formulation was approved on May 26, 2005[, expanding the drug's use to pre-dialysis patients and providing an alternative administration route for dialysis patients.]

8.2 Manufacturing and Marketing

The originator product, Zemplar®, was developed and is marketed by Abbott Laboratories, which later spun off its research-based pharmaceutical business into the company now known as AbbVie[.]

[Following the expiration of market exclusivity, the paricalcitol market has seen the entry of multiple generic manufacturers. The first generic versions of the IV solution were approved in the early 2010s, with Sandoz receiving approval in July 2011. The first generic oral capsules were approved in 2013, with Teva Pharmaceuticals being an early entrant. Today, numerous pharmaceutical companies manufacture and market generic paricalcitol in both oral and IV formulations, including]

Teva, Sandoz, Amneal Pharmaceuticals, Hikma Pharmaceuticals, Accord Healthcare[, and others, which has increased accessibility and reduced cost.]

9.0 Emerging Research and Future Directions

[While firmly established for its role in SHPT, the research landscape for paricalcitol is evolving. Investigations are increasingly focused on leveraging its mechanism of action for therapeutic benefits beyond mineral metabolism, exploring a potential "second act" for the drug as a pleiotropic modulator of complex disease states. This shift is driven by a deeper understanding of the VDR's ubiquitous expression and its critical role in regulating processes like inflammation, cellular proliferation, and immune response. The drug's conceptual role is thus expanding from a simple "hormone replacement" in CKD to an "active modulator" of pathophysiology in cardiovascular disease and oncology.]

9.1 Cardiovascular Applications

[The rationale for exploring paricalcitol in cardiovascular disease is strong. Vitamin D deficiency is an established risk factor for cardiovascular events, and the VDR is known to play a role in regulating the renin-angiotensin-aldosterone system (RAAS), systemic inflammation, and vascular cell health. Preclinical studies have yielded promising results, suggesting that paricalcitol can attenuate left ventricular abnormalities and, as previously noted, may possess a more favorable profile regarding vascular calcification compared to calcitriol.]

[This preclinical promise prompted clinical investigation. The NCT01073462 trial was an observational study designed to evaluate the effect of IV paricalcitol on cardiac morbidity in CKD Stage 5 patients over two years. Another study, NCT01792206, was a randomized trial designed to assess whether paricalcitol could improve endothelial function and reduce inflammation in patients with type 2 diabetes and CKD. However, translating these mechanistic benefits into clear clinical outcome improvements has proven challenging. As highlighted by a major systematic review and meta-analysis, when studied in the context of SHPT treatment, paricalcitol has not demonstrated a significant advantage over non-selective VDRAs in reducing all-cause mortality or cardiovascular calcification. This suggests that while a cardiovascular benefit may exist, it may be context-dependent or require trials specifically designed to test cardiovascular endpoints in high-risk populations, independent of PTH-lowering efficacy.]

9.2 Role in Oncology

[One of the most exciting areas of emerging research for paricalcitol is in oncology, particularly in the treatment of pancreatic cancer. The proposed mechanism is not one of direct cytotoxicity, but rather a sophisticated modulation of the tumor microenvironment. Pancreatic cancer is notoriously difficult to treat due to a dense, fibrotic stroma that forms a physical and biological barrier, protecting cancer cells from chemotherapy. Research from the Salk Institute has shown that VDR activation can "reprogram" the pancreatic stellate cells that are responsible for producing this stroma, essentially inactivating them and breaking down the tumor's protective shield.]

[This stromal-modulating effect could theoretically enhance the efficacy of other anti-cancer therapies. By making the tumor more permeable, paricalcitol could improve the delivery and effectiveness of standard cytotoxic agents like gemcitabine and nab-paclitaxel. This hypothesis was tested in the NCT03520790 clinical trial, a Phase 2 study combining paricalcitol with that chemotherapy regimen in metastatic pancreatic cancer. Although the trial was ultimately terminated due to futility based on the results of an unrelated, larger study, it represented a significant clinical exploration of this novel mechanism. Furthermore, researchers have proposed that this same mechanism could be used to enhance the efficacy of emerging treatments like oncolytic viruses, which also need to penetrate the stroma to be effective.]

9.3 Immunomodulatory and Other Potential Roles

[The pivotal role of the VDR in the immune system has opened another avenue of investigation. VDRs are expressed on most immune cells, including T-cells and antigen-presenting cells, and their activation is known to have potent anti-inflammatory and immunomodulatory effects. This has led to the consideration of vitamin D analogs, including paricalcitol, as potential therapeutic agents for a variety of autoimmune diseases. With more than 200 genes known to be regulated by the VDR and its expression in over 30 different cell types, the potential for VDR activators to influence a wide spectrum of physiological and pathological processes remains a fertile ground for future research and drug development.]

10.0 Conclusion

[Paricalcitol (Zemplar®) represents a significant and well-established therapeutic agent in the specialized field of nephrology. As a selective Vitamin D Receptor activator, it holds a firm place in the clinical armamentarium for the prevention and treatment of secondary hyperparathyroidism in patients with moderate to severe chronic kidney disease. Its development was a landmark in targeted drug design, engineered with specific structural modifications to uncouple potent parathyroid hormone suppression from the dose-limiting hypercalcemic and hyperphosphatemic effects of its non-selective predecessors. This provides clinicians with a valuable tool to manage the complex mineral and bone disorders inherent to CKD.]

[However, the clinical reality of paricalcitol is nuanced. While its mechanistic selectivity is clear at the preclinical level, large-scale meta-analyses have not consistently demonstrated a definitive superiority over older, active vitamin D analogs in terms of efficacy or safety in the broad CKD population. This highlights the complexity of treating these patients, where polypharmacy, dietary factors, and dialysis parameters can obscure the subtle benefits of a single agent. Its safety profile is predictable and manageable with rigorous monitoring, but its reliance on CYP3A4 for metabolism creates a significant potential for drug-drug interactions, demanding high clinical vigilance.]

[The future of paricalcitol is evolving beyond its foundational role. A growing body of research is exploring its pleiotropic effects, investigating its potential as an anti-inflammatory, anti-fibrotic, and immunomodulatory agent. Promising but still-developing research in cardiovascular disease and oncology—particularly its novel role in modulating the tumor stroma in pancreatic cancer—suggests that the full therapeutic potential of this selective VDR activator may not yet be fully realized. Paricalcitol thus stands as both a mature, essential therapy for a specific complication of CKD and a promising investigational compound with the potential to impact a broader range of complex human diseases.]

Works cited

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